Abstract A cure for osteoarthritis (OA) remains elusive. This is due in large part to two major obstacles, inability to detect OA sufficiently early before the onset of irreversible signs and recalcitrant symptoms, and inability to identify individuals at high risk of progression based on traditionally used metrics (age, sex, body mass index, knee pain and joint space width). The latter challenge is responsible for low powering of clinical trials and numerous drug trial failures. Using a systematic, unbiased and iterative approach, we have created a multiple reaction monitoring (MRM) proteomic panel for serum-based prediction of knee OA structural progression and diagnosis of knee OA. The selection of proteins was based on results of extensive discovery proteomic studies in synovial fluid, urine, and serum from knee OA radiographic progressors and non-progressors (with 3-4 year follow-up) and controls. The ultimate goals of this work are to qualify these new biomarker candidates in the contexts of knee OA progression and OA diagnosis in larger well-phenotyped cohorts from the Osteoarthritis Initiative, the Johnston County Osteoarthritis Project and the Chingford cohorts. With this further qualification, these new biomarker tools will be very significant for their potential utility for clinical trial and clinical use to inform strategies for phenotyping and earlier identification and treatment of OA patients. We also intend to pursue formal Food and Drug Administration (FDA) qualification of the optimal marker set yielded by this proposal to facilitate their use as drug development tools.